T cell receptor (TCR) mediated signal transduction involves a complex series of early events which culminate in cellular activation. The zeta subunit of the TCR has several characteristics which make it unique. It is structurally unrelated to the other invariant receptor subunits; it is expressed in natural killer cells in which other receptor components are not expressed; it undergoes tyrosine phosphorylation in response to T cell receptor activation; and has been shown to transduce signals independently of other receptor components. We are interested in understanding the molecular mechanisms whereby receptor occupancy is coupled to intracellular events. Our studies have concentrated on understanding the role that zeta plays both as an effector molecule and as a substrate for receptor activated protein tyrosine kinases. Our studies are carried out both in normal human natural killer cells and T cells as well as in the murine T lymphocyte hybridoma 2B4. Studies in 2B4 cells have been concentrated in two areas; systematic mutagenesis of the zeta subunit; and development of a permeabilized cell system for manipulation of the intracellular environment.